D Santi and others FSH and male infertility: 1–13 4:R46 Review a meta-analysis Open Access FSH treatment of male idiopathic infertility improves pregnancy rate: a meta-analysis D Santi1,2, A R M Granata2 and M Simoni1,2 Correspondence should be addressed 1Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena to D Santi and Reggio Emilia, Modena, Italy Email 2Unit of Endocrinology, Azienda USL of Modena, NOCSAE, Via P. Giardini 1355, 41126 Modena, Italy [email protected] Abstract Introduction: The aim of this study is to comprehensively evaluate whether FSH Key Words administration to the male partner of infertile couples improves pregnancy rate, " FSH spontaneously and/or after assisted reproductive techniques (ART). " male infertility Methods: Meta-analysis of controlled clinical trials in which FSH was administered for male " infertile couples idiopathic infertility, compared with placebo or no treatment. Randomization was not considered as an inclusion criterion. Results: We found 15 controlled clinical studies (614 men treated with FSH and 661 treated with placebo or untreated). Concerning the type of FSH, eight studies used recombinant FSH, whereas seven studies used purified FSH. Nine studies evaluated spontaneous pregnancy rate, resulting in an overall odds ratio (OR) of about 4.5 (CI: 2.17–9.33). Eight studies Endocrine Connections evaluated pregnancy rate after ART, showing a significant OR of 1.60 (CI: 1.08–2.37). Sub-dividing studies according to the FSH preparations (purified/recombinant), pregnancy rate improvement remained significant for each preparation. Eleven studies considered sperm quality after FSH treatment, finding a significant improvement of sperm concentration (2.66!106/ml, CI: 0.47–4.84), but not of concentration of sperm with progressive motility (1.22!106/ml, CI: K0.07 to 2.52). Three trials evaluated testicular volume, showing a non-significant increase in men treated (1.35 ml, CI: K0.44 to 3.14). Conclusion: The results of controlled clinical trials available in the literature indicate an improvement of pregnancy rate after FSH administration to the male partner of infertile couples, both spontaneously and after ART. However, the heterogeneity of studies, the high risk of bias and the lack of precise criteria to guide FSH administration limit the strength of these results. Future studies should be designed to identify the markers of FSH response which are helpful in the decision-making process. Meanwhile, the use of FSH in the treatment of male infertility should be cautious. Endocrine Connections (2015) 4, R46–R58 http://www.endocrineconnections.org Ñ 2015 Society for Endocrinology This work is licensed under a Creative Commons DOI: 10.1530/EC-15-0050 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 09/26/2021 10:44:54PM via free access Review D Santi and others FSH and male infertility: 2–13 4:R47 a meta-analysis Introduction Rationale Infertility is conventionally defined as a clinical condition before the cross-over was not available), and excluded all affecting a couple failing to conceive after a period of trials in which randomization was not carried out (15). 12 months of regular intercourse without contraception (1). Therefore, only six RCTs, the most recent thereof Male infertility plays a significant role in w50% of couples published in 2006 (16), were included in the meta- experiencing a delay in conceiving (2). A careful and analysis. The absence of further RCTs in this field of complete diagnostic workup allows for recognition of the medicine in the last decade reflects the difficulty of most important male infertility causes (3). However, the conducting a randomized approach in infertile couples, underlying pathophysiological mechanism remains idio- in which the woman is nearing the end of her reproductive pathic in about 30% of cases, which fall in the category of age, as a swift successful pregnancy is required. Finally, ’male idiopathic infertility’(2). The medical treatment of Attia et al. (15) evaluated pregnancy rate as an outcome of infertility may be specific or non-specific. Specific treat- FSH treatment without assessing separately purified and ments are used for certain etiologies, such as hypogonado- recombinant FSH formulations. tropic hypogonadism, male accessory gland infection, retrograde ejaculation, and positive antisperm antibody Objectives (4). Non-specific treatments are hormonal and non- hormonal therapies, proposed for the treatment of The aim of this study was to comprehensively evaluate idiopathic infertile men (5, 6). whether FSH administration to the male partner of infertile couples improves pregnancy rate, spontaneously Assisted reproductive techniques (ART) based on IVF and/or after ART, by performing a meta-analysis of all were introduced to clinical practice in 1978 (7), and controlled clinical trials. progressively extended its indication from female, tubal infertility to unexplained couple infertility. Currently, intracytoplasmatic-sperm injection (ICSI) is the most Materials and methods frequently used ART (8). The outcome of ICSI seems to be influenced by sperm structure and quality (9). Thus, it We performed a meta-analysis according to the Cochrane Endocrine Connections seems reasonable that an improvement in sperm quality Collaboration and PRISMA statement (17, 18). could effect ICSI outcomes. The empirical administration of follicle stimulating Data sources and searches hormone (FSH) to infertile men has been reported in the literature since 1991 to variably improve fertilization and We conducted a comprehensive literature search for pregnancy rate (10, 11). This therapy is popular in some English-language articles in MEDLINE (PubMed), EMBASE, countries, although doubts remain on its efficacy in the the Cochrane Library, SCOPUS and UpToDate. Search treatment of infertile men, particularly in the ART setting. key words were: FSH, FSH treatment, FSH therapy, follicle- A significant increase in pregnancy rate after IVF and male stimulating hormone, gonadotropin, infertility, male treatment with FSH was shown in some studies (12, 13), infertility, IVF, intracytoplasmatic sperm injection, IVF, while other trials did not find the same improvement (14). ICSI and the Boolean functions AND and OR. Recently, the Cochrane Collaboration estimated the overall effect of FSH treatment of the man in couples Study selection and inclusion criteria attending ART enrolled in randomised, controlled, clinical Types of studies " Controlled clinical trials in which trials (15). This meta-analysis demonstrates that FSH FSH was administered for male idiopathic infertility, treatment significantly improves spontaneous pregnancy compared with placebo or no treatment. Randomization rate, whereas no improvement of pregnancy rate is was not considered as inclusion criterion, thus both observed after ART, probably because only one random- randomized and non-RCTs were reviewed. ized clinical trial (RCT) was included (15). These results were obtained by evaluating only randomized, controlled, Type of participants " Men with idiopathic infertility clinical trials, using fixed and strict inclusion criteria (15). or subfertility. All semen abnormalities (from mild The authors excluded quasi-RCTs, cross-over trials (if data oligozoospermia to severe oligo-astheno-teratospermia) http://www.endocrineconnections.org Ñ 2015 Society for Endocrinology This work is licensed under a Creative Commons DOI: 10.1530/EC-15-0050 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 09/26/2021 10:44:54PM via free access Review D Santi and others FSH and male infertility: 3–13 4:R48 a meta-analysis were considered eligible, independently of the changes treatment allocation, iv) duration and type of treatment over time of the normality ranges for semen analysis by and follow-up phases, v) number of participants recruited, the World Health Organization (WHO). Azoospermic men analyzed or lost to follow-up, vi) timing of trial, vii) whether were not considered eligible. Controls were not treated or an intention to treat analysis was done, viii) whether a placebo-treated idiopathic infertile or sub-fertile men. power calculation was done, ix) source of funding, and No inclusion criteria were applied for the female partner x) criteria for including participants and assessing outcomes. of the infertile couple. Summary measures Type of interventions " Chronic treatment with any type of FSH, compared with placebo or no treatment. The primary outcome was pregnancy rate, evaluated as an odds ratio (OR) between treated and control men. Data collection process and quality Secondary outcomes were semen analysis parameters. Sperm quality (i.e. sperm concentration and progressive One author (D S) extracted the abstracts from all studies motility) and testicular volume were considered as mean found through the literature search. All abstracts were differences. Sperm motility was assessed as the number of evaluated for inclusion criteria and data were extracted progressive motile sperm, calculated considering only the from each study considered eligible, with regard to study percentage of sperm with progressive motility out of the design, year of publication, number of included/excluded total sperm number. subjects, number of dropped-out patients and the use of intention to treat/per protocol analysis. Furthermore, D S Data synthesis and